DLG5 variants contribute to Crohn disease risk in a Canadian population

Abstract

Variants in the gene encoding the DLG5 scaffolding protein have been reported to be associated with increased risk of inflammatory bowel disease (IBD) and particularly Crohn's disease (Crohn disease; CD). These findings have not been uniformly replicated in follow-up studies. In this study we genotyped a cohort of 402 Canadian CD and 179 ulcerative colitis (UC) patients and 537 healthy controls for three IBD/CD-associated DLG5 variants. Our data reveal that the common DLG5 haplotype (A), which was previously considered protective for IBD, is associated with modest increases in risk for IBD (P=0.02) and CD (P=0.04). The effects of haplotype copy number on risk for IBD were minor, with the odds ratio (ORs) being 1.37 for the heterozygous risk genotype and 1.7 for the homozygous risk genotype. While we were unable to replicate the proposed association between the DLG5 c.113G>A variant and IBD, an association of IBD (P=0.02) and CD (P=0.04) with the rarer c.4136C>A variant was replicated in this cohort. These associations were restricted to the non-Jewish subjects in this cohort and were not detected in the Ashkenazi Jewish population studied here. Within the non-Jewish group, no associations were detected between the DLG5 variants and specific phenotypic features, such as site of disease, and there was no evidence of epistasis between DLG5 and any of the CD-associated CARD15 or SLC22A4/A5 gene variants. Together, the results indicate a role for DLG5 variants in IBD susceptibility and suggest that further studies are warranted to evaluate this role in different IBD populations and to determine the functional pathways that couple DLG5 variants to IBD.

Genetic Association of DLG5 R30Q with Familial and Sporadic Inflammatory Bowel Disease in Men

“…The association of the R30Q variant with IBD has been supported in some studies [12,24,25,27], but failed to be replicated in others [28][29][30][31][32][33][34].…”

“…Stoll et al, [12] identified an IBD risk-associated DLG5 haplotype D that is uniquely distinguished by the 113A variant of R30Q. The association of R30Q with IBD has been replicated in other studies from several different patient populations [24][25][26]. Friedrichs et al, found a male-specific association of the R30Q variant with CD, with no association of the R30Q variant with women, nor with the entire sample of men and women [27].…”

The Genetics of Inflammatory Bowel Disease

“…MAGUK proteins are known to form scaffolds for other proteins involved in intracellular signal transduction and could therefore interfere with the integrity of the epithelial barrier. Since the publication of the index paper, germline variation of DLG5 has been studied in a large number of populations but replication has only been demonstrated in a few (77) (Table 3) (51,57,60,76,(79)(80)(81)(82)(83)(84)(85)(86)(87)(88). Whether true genetic heterogeneity, phenotypic differences between patient populations, and/or stratification of control groups are responsible for these discrepancies remains a subject of intense debate, but a meta-analysis of most published studies suggests it does not have a major role to play in IBD susceptibility (78).…”

Inflammatory bowel disease: Genetic and epidemiologic considerations

“…Present approaches have not been able to discern whether these other genes or the class Ⅱ genes are the true risk genes in the HLA locus. [79][80][81][82] , multiple polymorphisms in the MDR1/ABCB1 gene on chromosome 7q [83][84][85][86][87][88][89][90][91][92] , and polymorphisms in the DLG5 gene on chromosome 10q [70,[93][94][95][96][97][98][99][100][101][102] . (See section C.4.1.)…”